The desire to frequently drink large quantities of alcohol is a hallmark of alcoholism. Numerous studies have observed a significant correlation between life-long quantity of alcohol consumed and detriment to the body, including the degree of brain atrophy and risk for alcoholism. Thus, control of high alcohol drinking is an important problem that requires greater understanding at all scientific levels. This application explores new ways to increase our understanding of what controls high alcohol drinking. Preliminary data indicates that the anti-inflammatory antibiotic minocycline (50 mg/kg) is effective in reducing alcohol consumption in adult C57BL/6J (B6) mice when tested in two established drinking paradigms. However, it was not effective in adolescent B6 mice. This has led to our overarching hypothesis that neuroimmune cells and pathways have a significant role in mediating high alcohol drinking. We have devised 2 aims to test our hypothesis. Specific Aim 1 will test the hypothesis that functional microglia play a role in supporting high alcohol consumption. Specific Aim 2 is translational in nature and will test the hypothesis that the diminution of drinking effec of tetracyclines represents a unique activity based on specific structural features of the molecule. Our first aim will explore the requirement for brain microglial in mediating high alcohol drinking using an established animal model, the B6 mouse. These experiments will provide new information on the role of microglia in the brain under presumably non-injurious levels and durations of high alcohol intake. The results will impact not only alcohol research, but the study of reward mechanisms and glial biology. If, as we expect, these studies demonstrate the significance of brain microglia in alcohol consumption, they will potentially change the dogma regarding mechanisms that underlie a high alcohol drinking phenotype. Commensurate with the need for a greater understanding of what controls high alcohol drinking, medications that mitigate the desire to drink large quantities of alcohol are also needed. The second aim will explore the anti-drinking properties of other doses and dosing regimens of minocycline, as well as the efficacy of structurally-modified tetracyclines in our drinking-in-the-dark (DID) paradigm. As the first to test the efficacy of tetracyclines for the reduction of alcohol consumption, the follow-up studies proposed are exploratory and should lead to information that is mechanistic in nature, directly translational and important for the development of better medications. Overall, enthusiasm for the proposal was fairly high.